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Abstract Colitis-associated colorectal cancer (CAC) frequently develops in patients with inflammatory bowel disease (IBD) who have been exposed to a prolonged state of chronic inflammation. The investigation of pharmacological agents and their mechanisms to prevent precancerous lesions and inhibit their progression remains a significant focus and challenge in CAC research. Previous studies have demonstrated that vitexin effectively mitigates CAC, however, its precise mechanism of action warrants further exploration. This study reveals that the absence of the Vitamin D receptor (VDR) accelerates the progression from chronic colitis to colorectal cancer. Our findings indicate that vitexin can specifically target the VDR protein, facilitating its translocation into the cell nucleus to exert transcriptional activity. Additionally, through a co-culture model of macrophages and cancer cells, we observed that vitexin promotes the polarization of macrophages towards the M1 phenotype, a process that is dependent on VDR. Furthermore, ChIP-seq analysis revealed that vitexin regulates the transcriptional activation of phenazine biosynthesis-like domain protein (PBLD) via VDR. ChIP assays and dual luciferase reporter assays were employed to identify the functional PBLD regulatory region, confirming that the VDR/PBLD pathway is critical for vitexin-mediated regulation of macrophage polarization. Finally, in a mouse model with myeloid VDR gene knockout, we found that the protective effects of vitexin were abolished in mid-stage CAC. In summary, our study establishes that vitexin targets VDR and modulates macrophage polarization through the VDR/PBLD pathway, thereby alleviating the transition from chronic colitis to colorectal cancer.

Abstract Background tRNA-derived small RNAs (tsRNAs) are newly discovered non-coding RNA, which are generated from tRNAs and are reported to participate in several biological processes in diseases, especially cancer; however, the mechanism of tsRNA involvement in colorectal cancer (CRC) and 5-fluorouracil (5-FU) is still unclear. Methods RNA sequencing was performed to identify differential expression of tsRNAs in CRC tissues. CCK8, colony formation, transwell assays, and tumor sphere assays were used to investigate the role of tsRNA-GlyGCC in 5-FU resistance in CRC. TargetScan and miRanda were used to identify the target genes of tsRNA-GlyGCC. Biotin pull-down, RNA pull-down, luciferase assay, ChIP, and western blotting were used to explore the underlying molecular mechanisms of action of tsRNA-GlyGCC. The MeRIP assay was used to investigate the N(7)-methylguanosine RNA modification of tsRNA-GlyGCC. Results In this study, we uncovered the feature of tsRNAs in human CRC tissues and confirmed a specific 5’ half tRNA, 5’tiRNA-Gly-GCC (tsRNA-GlyGCC), which is upregulated in CRC tissues and modulated by METTL1-mediated N(7)-methylguanosine tRNA modification. In vitro and in vivo experiments revealed the oncogenic role of tsRNA-GlyGCC in 5-FU drug resistance in CRC. Remarkably, our results showed that tsRNA-GlyGCC modulated the JAK1/STAT6 signaling pathway by targeting SPIB. Poly (β-amino esters) were synthesized to assist the delivery of 5-FU and tsRNA-GlyGCC inhibitor, which effectively inhibited tumor growth and enhanced CRC sensitive to 5-FU without obvious adverse effects in subcutaneous tumor. Conclusions Our study revealed a specific tsRNA-GlyGCC-engaged pathway in CRC progression. Targeting tsRNA-GlyGCC in combination with 5-FU may provide a promising nanotherapeutic strategy for the treatment of 5-FU-resistance CRC. Graphical Abstract

Abstract Aggressive triple‐negative breast cancer (TNBC) still lacks approved targeted therapies, requiring more exploration of its underlying mechanisms. Previous studies have suggested a potential role of SAT1 (Spermidine/Spermine N1‐acetyltransferase 1) in cancer, which needs to be further elucidated in breast cancer. In this study, highly expressed SAT1 in TNBC signified worse patient prognoses. And SAT1 knockdown effectively inhibited the proliferation and migration abilities of TNBC cells in vitro and in vivo. In terms of mechanism, the transcription factor JUN enhanced SAT1 transcriptional activity by binding to its promoter region. Then, SAT1 protein in the cytoplasm engaged in directly binding with YBX1 for sustaining YBX1 protein stability via deubiquitylation mediated by the E3 ligase HERC5. Further, SAT1 was found to suppress autophagy remarkably via stabilization of mTOR mRNA with the accumulation of YBX1‐mediated methyl‐5‐cytosine (m5C) modification. These findings proved that SAT1 drives TNBC progression through the SAT1/YBX1/mTOR axis, which may provide a potential candidate for targeted therapy in advanced TNBC.

Abstract Ulcerative colitis (UC) is a complicated and recurrent intestinal disease. Currently available drugs for UC treatment are scarce, therefore, novel therapeutic drugs for the UC are urgently to be developed. Gingerenone A (GA) is a phenolic compound known for its anti‐inflammatory effect, but its effect on UC remains unknown. Here, it is shown that GA protects mice against UC, which is closely associated with inhibiting intestinal mucosal inflammation and enhancing intestinal barrier integrity in vivo and in vitro. Of note, RNA sequencing analysis demonstrates an evident correlation with IL‐17 signaling pathway after GA treatment, and this effect is further corroborated by Western blot. Mechanistically, GA directly interacts with IL‐17RA protein through pull‐down, surface plasmon resonance analysis and molecular dynamics simulation. Importantly, lentivirus‐mediated IL‐17RA/Act1 knock‐down or GA co‐treatment with brodalumab/ixekizumab significantly impairs the protective effects of GA against DSS‐induced inflammation and barrier dysfunction, suggesting a critical role of IL‐17RA signaling for GA‐mediated protection against UC. Overall, these results indicate that GA is an effective agent against UC mainly through the direct binding of IL‐17RA to inhibit inflammatory signaling activation.

Leonurine is an alkaloid unique to the Leonurus genus, which has many biological activities, such as uterine contraction, anti-inflammation, anti-oxidation, regulation of cell apoptosis, anti-tumor, angiogenesis, anti-platelet aggregation, and inhibition of vasoconstriction. This paper summarizes the extraction methods, synthetic pathways, biosynthetic mechanisms, pharmacokinetic properties, pharmacological effects in various diseases, toxicology, and clinical trials of leonurine. To facilitate a successful transition into clinical application, intensified efforts are required in several key areas: structural modifications of leonurine to optimize its properties, comprehensive pharmacokinetic assessments to understand its behavior within the body, thorough mechanistic studies to elucidate how it works at the molecular level, rigorous safety evaluations and toxicological investigations to ensure patient wellbeing, and meticulously conducted clinical trials to validate its efficacy and safety profile.

Abstract Breast cancer is the second leading cause of death in women worldwide, with triple-negative breast cancer (TNBC) having the worst prognosis. Although there are numerous studies on TNBC, there is no effective treatment for it, and it is still a major problem today. Studies on PIWI-interacting RNAs (piRNAs) are increasing and investigating the mechanism of piRNAs in the proliferation and metastasis of TNBC may lead to new potential treatment targets. Here, we identified a novel piRNA, piR-YBX1, which was downregulated in TNBC compared to matched normal breast tissue. Overexpression of piR-YBX1 significantly inhibited the proliferation, migration, invasion ability of TNBC cells both in vivo and in vitro. Mechanistically, piR-YBX1 could bind directly to mRNA of Y-box binding protein 1 (YBX1) and overexpression of piR-YBX1 downregulated YBX1 in both mRNA and protein levels, while the function of piR-YBX1 could be partly rescued by overexpression of YBX1. In addition, YBX1 could bind to RAF1 which is the key molecule in the MAPK signaling pathway, and overexpression of piR-YBX1 inhibited the p-MEK and p-ERK1/2, which can be reverted by YBX1. In conclusion, our findings discovered that the piR-YBX1/YBX1/MAPK axis suppresses the proliferation and metastasis of TNBC and therefore piR-YBX1 has the potential to be an effective therapeutic agent for breast cancer.

Abstract Over the past three decades, considerable efforts have been expended on understanding the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia, following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The aim of this review is to summarize the latest progress in our understanding of the involvement of the JAK/STAT signaling pathway in the development of leukemia. We also attempt to provide insights into the current use of JAK/STAT inhibitors in leukemia therapy and explore pertinent clinical trials in this field.

Abstract The incidence of nasopharyngeal carcinoma (NPC) exhibits significant variations across different ethnic groups and geographical regions, with Southeast Asia and North Africa being endemic areas. Of note, Epstein-Barr virus (EBV) infection is closely associated with almost all of the undifferentiated NPC cases. Over the past three decades, radiation therapy and chemotherapy have formed the cornerstone of NPC treatment. However, recent advancements in immunotherapy have introduced a range of promising approaches for managing NPC. In light of these developments, it has become evident that a deeper understanding of the tumor microenvironment (TME) is crucial. The TME serves a dual function, acting as a promoter of tumorigenesis while also orchestrating immunosuppression, thereby facilitating cancer progression and enabling immune evasion. Consequently, a comprehensive comprehension of the TME and its intricate involvement in the initiation, progression, and metastasis of NPC is imperative for the development of effective anticancer drugs. Moreover, given the complexity of TME and the inter-patient heterogeneity, personalized treatment should be designed to maximize therapeutic efficacy and circumvent drug resistance. This review aims to provide an in-depth exploration of the TME within the context of EBV-induced NPC, with a particular emphasis on its pivotal role in regulating intercellular communication and shaping treatment responses. Additionally, the review offers a concise summary of drug resistance mechanisms and potential strategies for their reversal, specifically in relation to chemoradiation therapy, targeted therapy, and immunotherapy. Furthermore, recent advances in clinical trials pertaining to NPC are also discussed.

Abstract The heterogeneity of macrophages influences the response to immune checkpoint inhibitor (ICI) therapy. However, few studies explore the impact of APOE+ macrophages on ICI therapy using single‐cell RNA sequencing (scRNA‐seq) and machine learning methods. The scRNA‐seq and bulk RNA‐seq data are Integrated to construct an M.Sig model for predicting ICI response based on the distinct molecular signatures of macrophage and machine learning algorithms. Comprehensive single‐cell analysis as well as in vivo and in vitro experiments are applied to explore the potential mechanisms of the APOE+ macrophage in affecting ICI response. The M.Sig model shows clear advantages in predicting the efficacy and prognosis of ICI therapy in pan‐cancer patients. The proportion of APOE+ macrophages is higher in ICI non‐responders of triple‐negative breast cancer compared with responders, and the interaction and longer distance between APOE+ macrophages and CD8+ exhausted T (Tex) cells affecting ICI response is confirmed by multiplex immunohistochemistry. In a 4T1 tumor‐bearing mice model, the APOE inhibitor combined with ICI treatment shows the best efficacy. The M.Sig model using real‐world immunotherapy data accurately predicts the ICI response of pan‐cancer, which may be associated with the interaction between APOE+ macrophages and CD8+ Tex cells.

Abstract The proteasome inhibitor bortezomib (BTZ) is the first‐line therapy for multiple myeloma (MM). BTZ resistance largely limits its clinical application in MM. Interleukin‐33 (IL‐33) exerts antitumor effects through various mechanisms, including enhancing antitumor immunity and promoting the apoptosis of cancer cells. Here, the synergistic anti‐MM effect of IL‐33 and BTZ was verified, and the underlying mechanisms were elucidated. Bioinformatic analysis indicated that IL‐33 expression levels were downregulated in MM, and that BTZ‐treated MM patients with high IL‐33 levels had better prognosis than those with low IL‐33 levels. Moreover, the patients with high IL‐33 levels had a better treatment response to BTZ. Further immune analysis suggested that IL‐33 can enhance the anti‐MM immunity. IL‐33 and BTZ synergistically inhibited proliferation and induced apoptosis of MM cells, which was mediated by the excessive accumulation of cellular reactive oxygen species (ROS). Furthermore, increased ROS hindered the nuclear translocation of NF‐κB‐p65, thereby decreasing the transcription of target stemness‐related genes (SOX2, MYC, and OCT3/4). These effects induced by the combination therapy could be reversed by eliminating ROS by N‐acetylcysteine. In conclusion, our results indicated that IL‐33 enhanced the sensitivity of MM to BTZ through ROS‐mediated inhibition of nuclear factor kappa‐B (NF‐κB) signal and stemness properties.

The therapeutic effect of chemotherapy and targeted therapy are known to be limited by drug resistance. Substantial evidence has shown that ATP-binding cassette (ABC) transporters P-gp and BCRP are significant contributors to multidrug resistance (MDR) in cancer cells. In this study, we demonstrated that a clinical-staged ATR inhibitor ceralasertib is susceptible to P-gp and BCRP-mediated MDR. The drug resistant cancer cells were less sensitive to ceralasertib compared to the parental cells. Moreover, ceralasertib resistance can be reversed by inhibiting the drug efflux activity of P-gp and BCRP. Interestingly, ceralasertib was able to downregulate the level of P-gp but not BCRP, suggesting a potential regulation between ATR signaling and P-gp expression. Furthermore, computational docking analysis predicted high affinities between ceralasertib and the drug-binding sites of P-gp and BCRP. In summary, overexpression of P-gp and BCRP are sufficient to confer cancer cells resistance to ceralasertib, underscoring their role as biomarkers for therapeutic efficacy.

BackgroundThe Y-box-binding proteins (YBX) act as a multifunctional role in tumor progression, metastasis, drug resistance by regulating the transcription and translation process. Nevertheless, their functions in a pan-cancer setting remain unclear.MethodsThis study examined the clinical features expression, prognostic value, mutations, along with methylation patterns of three genes from the YBX family (YBX1, YBX2, and YBX3) in 28 different types of cancer. Data used for analysis were obtained from Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. A novel YBXs score was created using the ssGSEA algorithm for the single sample gene set enrichment analysis. Additionally, we explored the YBXs score’s association with the tumor microenvironment (TME), response to various treatments, and drug resistance.ResultsOur analysis revealed that YBX family genes contribute to tumor progression and are indicative of prognosis in diverse cancer types. We determined that the YBXs score correlates significantly with numerous malignant pathways in pan-cancer. Moreover, this score is also linked with multiple immune-related characteristics. The YBXs score proved to be an effective predictor for the efficacy of a range of treatments in various cancers, particularly immunotherapy. To summarize, the involvement of YBX family genes is vital in pan-cancer and exhibits a significant association with TME. An elevated YBXs score indicates an immune-activated TME and responsiveness to diverse therapies, highlighting its potential as a biomarker in individuals with tumors. Finally, experimental validations were conducted to explore that YBX2 might be a potential biomarker in liver cancer.ConclusionThe creation of YBXs score in our study offered new insights into further studies. Besides, YBX2 was found as a potential therapeutic target, significantly contributing to the improvement of HCC diagnosis and treatment strategies.

Abstract Aurora-A kinase interacting protein 1 (AURKAIP1) has been proved to take an intermediary role in cancer by functioning as a negative regulator of Aurora-A kinase. However, it remains unclear whether and how AURKAIP1 itself would directly engage in regulating malignancies. The expression levels of AURKAIP1 were detected in triple negative breast cancer (TNBC) by immunohistochemistry and western blots. The CCK8, colony formation assays and nude mouse model were conducted to determine cell proliferation whereas transwell and wound healing assays were performed to observe cell migration. The interaction of AURKAIP1 and DEAD-box helicase 5 (DDX5) were verified through co-immunoprecipitation and successively western blots. From the results, we found that AURKAIP1 was explicitly upregulated in TNBC, which was positively associated with tumor size, lymph node metastases, pathological stage and unfavorable prognosis. AURKAIP1 silencing markedly inhibited TNBC cell proliferation and migration in vitro and in vivo. AURKAIP1 directly interacted with and stabilized DDX5 protein by preventing ubiquitination and degradation, and DDX5 overexpression successfully reversed proliferation inhibition induced by knockdown of AURKAIP1. Consequently, AURKAIP1 silencing suppressed the activity of Wnt/β-catenin signaling in a DDX5-dependent manner. Our study may primarily disclose the molecular mechanism by which AURKAIP1/DDX5/β-catenin axis modulated TNBC progression, indicating that AURKAIP1 might serve as a therapeutic target as well as a TNBC-specific biomarker for prognosis.

Abstract Background Histone chaperones (HCs) are crucial for governing genome stability and gene expression in multiple cancers. However, the functioning of HCs in the tumor microenvironment (TME) is still not clearly understood. Methods Self-tested single-cell RNA-seq data derived from 6 breast cancer (BC) patients with brain and liver metastases were reanalyzed by nonnegative matrix factorization (NMF) algorithm for 36 HCs. TME subclusters were observed with BC and immunotherapy public cohorts to assess their prognosis and immune response. The biological effect of HSPA8, one of the HCs, was verified by transwell assay and wound-healing assays. Results Cells including fibroblasts, macrophages, B cells, and T cells, were classified into various subclusters based on marker genes. Additionally, it showed that HCs might be strongly associated with biological and clinical features of BC metastases, along with the pseudotime trajectory of each TME cell type. Besides, the results of bulk-seq analysis revealed that TME cell subclusters mediated by HCs distinguished significant prognostic value for BC patients and were relevant to patients’ immunotherapy responses, especially for B cells and macrophages. In particular, CellChat analysis exhibited that HCs-related TME cell subclusters revealed extensive and diverse interactions with malignant cells. Finally, transwell and wound-healing assays exhibited that HSPA8 deficiency inhibited BC cell migration and invasion. Conclusions Collectively, our study first dissected HCs-guided intercellular communication of TME that contribute to BC metastases.

Chikungunya virus (CHIKV) is a reemerging arbovirus causing disease on a global scale, and the potential for its epidemics remains high. CHIKV has caused millions of cases and heavy economic burdens around the world, while there are no available approved antiviral therapies to date. In this study, nifuroxazide, an FDA-approved antibiotic for acute diarrhea or colitis, was found to significantly inhibit a variety of arboviruses, although its antiviral activity varied among different target cell types. Nifuroxazide exhibited relatively high inhibitory efficiency in yellow fever virus (YFV) infection of the hepatoma cell line Huh7, tick-borne encephalitis virus (TBEV) and west nile virus (WNV) infection of the vascular endothelial cell line HUVEC, and CHIKV infection of both Huh7 cells and HUVECs, while it barely affected the viral invasion of neurons. Further systematic studies on the action stage of nifuroxazide showed that nifuroxazide mainly inhibited in the viral replication stage. In vivo, nifuroxazide significantly reduced the viral load in muscles and protected mice from CHIKV-induced footpad swelling, an inflammation injury within the arthrosis of infected mice. These results suggest that nifuroxazide has a potential clinical application as an antiviral drug, such as in the treatment of CHIKV infection.

CDK8 is an important member of the cyclin-dependent kinase family associated with transcription and acts as a key “molecular switch” in the Mediator complex. CDK8 regulates gene expression by phosphorylating transcription factors and can control the transcription process through Mediator complex. Previous studies confirmed that CDK8 is an important oncogenic factor, making it a potential tumor biomarker and a promising target for tumor therapy. However, CDK8 has also been confirmed to be a tumor suppressor, indicating that it not only promotes the development of tumors but may also be involved in tumor suppression. Therefore, the dual role of CDK8 in the process of tumor development is worth further exploration and summary. This comprehensive review delves into the intricate involvement of CDK8 in transcription-related processes, as well as its role in signaling pathways related to tumorigenesis, with a focus on its critical part in driving cancer progression.

Introduction:Despite the abundance of research indicating the participation of immune cells in prostate cancer development, establishing a definitive cause-and-effect relationship has proven to be a difficult undertaking.Methods:This study employs Mendelian randomization (MR), leveraging genetic variables related to immune cells from publicly available genome-wide association studies (GWAS), to investigate this association. The primary analytical method used in this study is inverse variance weighting (IVW) analysis. Comprehensive sensitivity analyses were conducted to assess the heterogeneity and horizontal pleiotropy of the results.Results:The study identifies four immune cell traits as causally contributing to prostate cancer risk, including CD127- CD8+ T cell %CD8+ T cell (OR = 1.0042, 95%CI:1.0011–1.0073, p = 0.0077), CD45RA on CD39+ resting CD4 regulatory T cell (OR = 1.0029, 95%CI:1.0008–1.0050, p = 0.0065), CD62L− Dendritic Cell Absolute Count (OR = 1.0016; 95%CI:1.0005–1.0026; p = 0.0039), CX3CR1 on CD14+ CD16− monocyte (OR = 1.0024, 95%CI:1.0007–1.0040, p = 0.0060). Additionally, two immune cell traits are identified as causally protective factors: CD4 on monocyte (OR = 0.9975, 95%CI:0.9958–0.9992, p = 0.0047), FSC-A on plasmacytoid Dendritic Cell (OR = 0.9983, 95%CI:0.9970–0.9995, p = 0.0070). Sensitivity analyses indicated no horizontal pleiotropy.Discussion:Our MR study provide evidence for a causal relationship between immune cells and prostate cancer, holding implications for clinical diagnosis and treatment.

Abstract Disruption of disulfide homeostasis during biological processes can have fatal consequences. Excess disulfides induce cell death in a novel manner, termed as “disulfidptosis.” However, the specific mechanism of disulfidptosis has not yet been elucidated. To determine the cancer types sensitive to disulfidptosis and outline the corresponding treatment strategies, we firstly investigated the crucial functions of disulfidptosis regulators pan‐cancer at multi‐omics levels. We found that different tumor types expressed dysregulated levels of disulfidptosis regulators, most of which had an impact on tumor prognosis. Moreover, we calculated the disulfidptosis activity score in tumors and validated it using multiple independent datasets. Additionally, we found that disulfidptosis activity was correlated with classic biological processes and pathways in various cancers. Disulfidptosis activity was also associated with tumor immune characteristics and could predict immunotherapy outcomes. Notably, the disulfidptosis regulator, glycogen synthase 1 (GYS1), was identified as a promising target for triple‐negative breast cancer and validated via in vitro and in vivo experiments. In conclusion, our study elucidated the complex molecular phenotypes and clinicopathological correlations of disulfidptosis regulators in tumors, laying a solid foundation for the development of disulfidptosis‐targeting strategies for cancer treatment.

Abstract Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune‐related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota‐derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.

Triple-negative breast cancer (TNBC) is currently the worst prognostic subtype of breast cancer, and there is no effective treatment other than chemotherapy. Processing of precursors 1 (POP1) is the most substantially up-regulated RNA-binding protein (RBP) in TNBC. However, the role of POP1 in TNBC remains clarified. A series of molecular biological experiments in vitro and in vivo and clinical correlation analyses were conducted to clarify the biological function and regulatory mechanism of POP1 in TNBC. Here, we identified that POP1 is significantly up-regulated in TNBC and associated with poor prognosis. We further demonstrate that POP1 promotes the cell cycle and proliferation of TNBC in vitro and vivo. Mechanistically, POP1 directly binds to the coding sequence (CDS) region of CDKN1A mRNA and degrades it. The degradation process depends on the N6-methyladenosine (m6A) modification at the 497th site of CDKN1A and the recognition of this modification by YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Moreover, the m6A inhibitor STM2457 potently impaired the proliferation of POP1-overexpressed TNBC cells and improved the sensitivity to paclitaxel. In summary, our findings reveal the pivotal role of POP1 in promoting TNBC proliferation by degrading the mRNA of CDKN1A and that inhibition of m6A with STM2457 is a promising therapeutic strategy for TNBC.

Abstract Breast cancer is the second leading cause of death for women worldwide. The heterogeneity of this disease presents a big challenge in its therapeutic management. However, recent advances in molecular biology and immunology enable to develop highly targeted therapies for many forms of breast cancer. The primary objective of targeted therapy is to inhibit a specific target/molecule that supports tumor progression. Ak strain transforming, cyclin-dependent kinases, poly (ADP-ribose) polymerase, and different growth factors have emerged as potential therapeutic targets for specific breast cancer subtypes. Many targeted drugs are currently undergoing clinical trials, and some have already received the FDA approval as monotherapy or in combination with other drugs for the treatment of different forms of breast cancer. However, the targeted drugs have yet to achieve therapeutic promise against triple-negative breast cancer (TNBC). In this aspect, immune therapy has come up as a promising therapeutic approach specifically for TNBC patients. Different immunotherapeutic modalities including immune-checkpoint blockade, vaccination, and adoptive cell transfer have been extensively studied in the clinical setting of breast cancer, especially in TNBC patients. The FDA has already approved some immune-checkpoint blockers in combination with chemotherapeutic drugs to treat TNBC and several trials are ongoing. This review provides an overview of clinical developments and recent advancements in targeted therapies and immunotherapies for breast cancer treatment. The successes, challenges, and prospects were critically discussed to portray their profound prospects.

Abstract Breast cancer (BC) is the most common cancer and the top cause of female mortality worldwide. The prognosis for patients with breast cancer liver metastasis (BCLM) remains poor. Emerging studies suggest that circular RNAs (circRNAs) are associated with the progression of BC. Exploration of circRNAs presents a promising avenue for identifying metastasis-targeting agents and improving the prognosis of patients with BCLM. Microarray and bioinformatic analyses were used to analyze differentially expressed circRNAs between three pairs of BCLM and primary BC. The roles of hsa_circ_0060467 (circMYBL2) and its target gene E2F1 in BC cells were explored by multiple functional experiments. And xenograft mouse models and hepatic metastases of BC hemi-spleen models were used to illustrate the function of circMYBL2 in vivo. The intrinsic molecular mechanism involving circMYBL2 was confirmed by bioinformatics analyses, RIP assays, CHIRP assays, luciferase reporter assays, and rescue experiments. CircMYBL2 was overexpressed in BCLM tissues and BC cells. Functionally, circMYBL2 can facilitate the proliferation and liver metastasis of BC. Mechanistically, circMYBL2 upregulated the transcription factor E2F1 by sponging miR-1205 and complexing with eukaryotic translation initiation factor 4A3 (eIF4A3) and then facilitated the epithelial-mesenchymal transition (EMT) process in BC cells. Our findings showed that circMYBL2 promoted the tumorigenesis and aggressiveness of BC through the circMYBL2/miR-1205/E2F1 and circMYBL2/eIF4A3/E2F1 axes, which may provide a novel targeted therapy for patients with BCLM.

Colorectal cancer (CRC) is one of the main fatal cancers. Cell signaling such as Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling substantially influences the process of gene expression and cell growth. Long non-coding RNAs (lncRNAs) play regulatory roles in cell signaling, cell proliferation, and cancer fate. Hence, lncRNAs can be considered biomarkers in cancers. The inhibitory or activating effects of different lncRNAs on the JAK/STAT pathway regulate cancer cell proliferation or tumor suppression. Additionally, lncRNAs regulate immune responses which play a role in immunotherapy. Mechanisms of lncRNAs in CRC via JAK/STAT regulation mainly include cell proliferation, invasion, metastasis, apoptosis, adhesion, and control of inflammation. More profound findings are warranted to specifically target the lncRNAs in terms of activation or suppression in hindering CRC cell proliferation. Here, to understand the lncRNA cross-talk in CRC through the JAK/STAT signaling pathway, we collected the related in vitro and in vivo data. Future insights may pave the way for the development of novel diagnostic tools, therapeutic interventions, and personalized treatment strategies for CRC patients.

Introduction: Type IV secretion systems (T4SSs) are integral parts of the conjugation process in enteric bacteria. These secretion systems are encoded within the transfer (tra) regions of plasmids, including those that harbor antimicrobial resistance (AMR) genes. The conjugal transfer of resistance plasmids can lead to the dissemination of AMR among bacterial populations.Methods: To facilitate the analyses of the conjugation-associated genes, transfer related genes associated with key groups of AMR plasmids were identified, extracted from GenBank and used to generate a plasmid transfer gene dataset that is part of the Virulence and Plasmid Transfer Factor Database at FDA, serving as the foundation for computational tools for the comparison of the conjugal transfer genes. To assess the genetic feature of the transfer gene database, genes/proteins of the same name (e.g., traI/TraI) or predicted function (VirD4 ATPase homologs) were compared across the different plasmid types to assess sequence diversity. Two analyses tools, the Plasmid Transfer Factor Profile Assessment and Plasmid Transfer Factor Comparison tools, were developed to evaluate the transfer genes located on plasmids and to facilitate the comparison of plasmids from multiple sequence files. To assess the database and associated tools, plasmid, and whole genome sequencing (WGS) data were extracted from GenBank and previous WGS experiments in our lab and assessed using the analysis tools.Results: Overall, the plasmid transfer database and associated tools proved to be very useful for evaluating the different plasmid types, their association with T4SSs, and increased our understanding how conjugative plasmids contribute to the dissemination of AMR genes.

Cancer stands as a prominent contributor to global mortality rates, necessitating immediate attention toward the exploration of its treatment options. Extracellular vesicles have been investigated as a potential cancer therapy in recent years. Among them, exosomes, as cell-derived nanovesicles with functions such as immunogenicity and molecular transfer, offer new possibilities for immunotherapy of cancer. However, multiple studies have shown that exosomes of different cellular origins have different therapeutic effects. The immunomodulatory effects of exosomes include but are not limited to inhibiting or promoting the onset of immune responses, regulating the function of molecular signaling pathways, and serving as carriers of antitumor drugs. Therefore, this mini-review attempts to summarize and evaluate the development of strategies for using exosomes to package exogenous cargos to promote immunotherapy in cancer.

Thymic epithelial tumors (TETs) are a rare and diverse group of neoplasms characterized by distinct molecular signatures. This review delves into the complex molecular networks of TETs, highlighting key aspects such as chromosomal abnormalities, molecular subtypes, aberrant gene mutations and expressions, structural gene rearrangements, and epigenetic changes. Additionally, the influence of the dynamic tumor microenvironment on TET behavior and therapeutic responses is examined. A thorough understanding of these facets elucidates TET pathogenesis, offering avenues for enhancing diagnostic accuracy, refining prognostic assessments, and tailoring targeted therapeutic strategies. Our review underscores the importance of deciphering TETs’ unique molecular signatures to advance personalized treatment paradigms and improve patient outcomes. We also discuss future research directions and anticipated challenges in this intriguing field.

Abstract Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS‐CoV‐2 infection via upregulating angiotensin‐converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene trans‐activates the promoters of ACE2 and TMPRSS2 by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in ACE2 and TMPRSS2. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS‐CoV‐2 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown or interferon‐λ2/λ3 stimulation downregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS‐CoV‐2 infection by boosting NR4A2‐induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS‐CoV‐2 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.

Introduction: Previous studies indicated that Wuda Granule (WDG) has been applied in the treatment of gastrointestinal motility disorder (GMD), but the effect and underlying mechanisms is yet to be elucidated. This study aimed to explore the mechanism and pharmacological effect of WDG for GMD via network analysis, verification of animal experiments and clinical experiments.Methods: The chemical components of WDG were identified from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP, http://lsp.nwu.edu.cn/index.php), and the Encyclopedia of Traditional Chinese Medicine (ETCM, http://www.tcmip.cn/ETCM/index.php/Home/Index/) according to oral bioavailability (OB) ≥ 20% and drug-likeness (DL) ≥ 0.10. The targets of WDG compounds were retrieved from the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) and targets related to GMD were retrieved from GeneCards database (https://www.genecards.org/). Network analysis were performed to screen the key active compounds of WDG and its hub targets. Then the pharmacological effect of WDG were verified via vivo experiments in rats and clinical experiments.Results: The results showed that 117 effective active compounds of WDG were screened and 494 targets of WDG compounds targeting GMD were selected. These targets were involved in the biological process of inflammatory regulation and the regulation of gastrointestinal motility. The mechanism was mainly involved in the regulation of PI3K-Akt signaling pathway and Rap1 signaling pathway. In addition, molecular docking analysis suggested that eight key active compounds of WDG may be mainly responsible for the effect of WDG on GMD by targeting HARS, AKT, and PIK3CA, respectively. Animal experiments and clinical trials both suggested that WDG could exert therapeutical effect on GMD via inhibiting inflammation and promoting gastrointestinal motility, it could also improve digestive function of patients with laparoscopic colorectal cancer after surgery.Conclusion: This study was the first to demonstrate that WDG improved GMD mainly via inhibiting inflammatory level and promoting gastrointestinal motility, providing new insights for the understanding of WDG for GMD, inspiration for future research and reference for clinical strategy in terms of the treatment of GMD.

Yellow fever virus (YFV) infection is a major public concern that threatens a large population in South America and Africa. No specific anti-YFV drugs are available till now. Here, we report that rifapentine is a potent YFV inhibitor in various cell lines by high-throughput drugs screening, acting at both cell entry and replication steps. Kinetic test and binding assay suggest that rifapentine interferes the viral attachment to the target cells. The application of YFV replicon and surface plasmon resonance assay indicates that rifapentine suppresses viral replication by binding to the RNA-dependent RNA polymerase (RdRp) domain of viral nonstructural protein NS5. Further molecular docking suggests that it might interact with the active centre of RdRp. Rifapentine significantly improves the survival rate, alleviates clinical signs, and reduces virus load and injury in targeted organs both in YFV-infected type I interferon receptor knockout A129−/− and wild-type C57 mice. The antiviral effect in vivo is robust during both prophylactic intervention and therapeutic treatment, and the activity is superior to sofosbuvir, a previously reported YFV inhibitor in mice. Our data show that rifapentine may serve as an effective anti-YFV agent, providing promising prospects in the development of YFV pharmacotherapy.

Abstract Background Metastasis of breast cancer have caused the majority of cancer-related death worldwide. The circRNAs are associated with tumorigenesis and metastasis in breast cancer according to recent research. However, the biological mechanism of circRNAs in liver metastatic breast cancer remains ambiguous yet. Methods Microarray analysis of three pairs of primary BC tissues and matched hepatic metastatic specimens identified circEZH2. We used RT-qPCR and FISH assays to confirm circEZH2 existence, characteristics, and expression. Both in vivo and in vitro, circEZH2 played an oncogenic role which promoted metastasis as well. A range of bioinformatic analysis, Western blot, RNA pull-down, RIP, ChIP, and animal experiments were used to define the feedback loop involving FUS, circEZH2, miR-217-5p, KLF5, FUS, CXCR4 as well as epithelial and mesenchymal transition. Results In our research, circEZH2 was proved to be upregulated in liver metastases in BC and predicted the worse prognosis in breast cancer patients. Overexpression of circEZH2 notably accentuated the vitality and invasion of BC cells, whereas knockdown of circEZH2 elicited the literally opposite effects. Besides, overexpressed circEZH2 promoted tumorigenesis and liver metastasis in vivo. Moreover, circEZH2 could adsorb miR-217-5p to upregulate KLF5 thus leading to activate FUS transcription which would facilitate the back-splicing program of circEZH2. Meanwhile, KLF5 could upregulated CXCR4 transcriptionally to accelerate epithelial and mesenchymal transition of breast cancer. Conclusions Consequently, a novel feedback loop FUS/circEZH2/KLF5/CXCR4 was established while circEZH2 could be novel biomarker and potential target for BC patients’ therapy.

Abstract In the central nervous system diseases, glioma is one of the most common malignancies around the world. Despite the recent improvements in therapies for glioma, the prognosis of some high‐risk glioma remains poor. In glioma, isoliquiritigenin (ISL) is reported to have antioxidative and antitumor activities. However, the potential mechanisms between ISL and circle RNAs (circRNAs) in the glioma tumorigenesis process have not yet been reported. Here, we treated glioma cells with ISL, and circRNA expression levels were detected. Circ0030018 was found significantly downregulated by ISL. Therefore, we explored circ0030018 expression profiles and functions in glioma, finding that circ0030018 was evidently overexpressed in glioma cell lines. Colony formation, CCK‐8, and transwell assay made clear that circ0030018 silencing dramatically cut down glioma growth and invasion. Moreover, ROS level was detected to find that circ0030018 silence remarkably enhanced cell oxidative stress in glioma. Mechanism studies were conducted to investigate the underlying basis of circ0030018 function in glioma, unveiling that circ0030018 realized its functions partially through the miR‐1236/HER2 signaling in glioma. In conclusion, our study investigated the roles and mechanisms of the ISL on the circ0030018/miR‐1236/HER2 pathway in glioma tumorigenesis and progression. Circ0030018 could act as the prospective biologic signature or therapeutic target for glioma.

Anti-HER2 resistance causes treatment failure in HER2-positive breast cancers. Here the authors identify FGFR4 as one of the vulnerabilities of anti-HER2 resistant breast cancer and show that FGRR4 inhibition enhances sensitivity to anti-HER2 treatment in these resistant cells by triggering ferroptosis.

Triple-negative breast cancer (TNBC) is considered as the most hazardous subtype of breast cancer owing to its accelerated progression, enormous metastatic potential, and refractoriness to standard treatments. Long noncoding RNAs (lncRNAs) are extremely intricate in tumorigenesis and cancerous metastasis. Nonetheless, their roles in the initiation and augmentation of TNBC remain elusive. Here, in silico analysis and validation experiments were utilized to analyze the expression pattern of clinically effective lncRNAs in TNBC, among which a protective lncRNA LYPLAL1-DT was essentially curbed in TNBC samples and indicated a favorable prognosis. Gain- and loss-of-function assays elucidated that LYPLAL1-DT considerably attenuated the proliferative and metastatic properties along with epithelial-mesenchymal transition of TNBC cells. Moreover, forkhead box O1 (FOXO1) was validated to modulate the transcription of LYPLAL1-DT. Mechanistically, LYPLAL1-DT impinged on the malignancy of TNBC mainly by restraining the aberrant reactivation of the Wnt/β-catenin signaling pathway, explicitly destabilizing and diminishing β-catenin protein by interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK) and constricting the formation of the hnRNPK/β-catenin complex. Conclusively, our present research revealed the anti-oncogenic effects of LYPLAL1-DT in TNBC, unraveling the molecular mechanisms of the FOXO1/LYPLAL1-DT/hnRNPK/β-catenin signaling axis, which shed innovative light on the potential curative medicine of TNBC.

Circular RNAs (circRNAs) are noncoding RNAs that form covalently closed loop structures. CircRNAs are dysregulated in cancer and play key roles in tumorigenesis, diagnosis, and tumor therapy. CircRNAs function as competing endogenous RNAs or microRNA sponges that regulate transcription and splicing, binding to proteins, and translation. CircRNAs may serve as novel biomarkers for cancer diagnosis, and they show potential as therapeutic targets in cancers including breast cancer (BC). In women, BC is the most common malignant tumor worldwide and the second leading cause of cancer death. Although evidence indicates that circRNAs play a critical role in BC, the mechanisms regulating the function of circRNAs in BC remain poorly understood. Here, we provide literature review aiming to clarify the role of circRNAs in BC and summarize the latest research. We provide a systematic overview of the biogenesis and biological functions of circRNAs, elaborate on the functional roles of circRNAs in BC, and highlight the value of circRNAs as diagnostic and therapeutic targets in BC.

Abstract Background Metastasis causes the majority of cancer-related deaths worldwide. Increasing studies have revealed that circRNAs are associated with the carcinogenesis and metastasis of many cancers. Nevertheless, the biological mechanisms of circRNAs in breast cancer (BC) liver metastasis remain extremely ambiguous. Methods In this study, we identified circROBO1 from three pairs of primary BC and metastatic liver sites by RNA sequencing. FISH assays and RT-qPCR were conducted to validate the existence and expression of circROBO1. The oncogenic role of circROBO1 was demonstrated both in vitro and in vivo. Western blot, ChIP, RIP, RNA pull-down, and dual-luciferase reporter assays were used to confirm the interaction of the feedback loop among circROBO1, miR-217-5p, KLF5, and FUS. Meanwhile, the regulation of selective autophagy was investigated by immunofluorescence, CoIP, and western blot. Results In this study, upregulated expression of circROBO1 was found in BC-derived liver metastases and was correlated with poor prognosis. Knockdown of circROBO1 strikingly inhibited the proliferation, migration, and invasion of BC cells, whereas overexpression of circROBO1 showed the opposite effects. Moreover, overexpression of circROBO1 promoted tumor growth and liver metastasis in vivo. Further research revealed that circROBO1 could upregulate KLF5 by sponging miR-217-5p, allowing KLF5 to activate the transcription of FUS, which would promote the back splicing of circROBO1. Therefore, a positive feedback loop comprising circROBO1/KLF5/FUS was formed. More importantly, we found that circROBO1 inhibited selective autophagy of afadin by upregulating KLF5. Conclusions Our results demonstrated that circROBO1 facilitates the carcinogenesis and liver metastasis of BC through the circROBO1/KLF5/FUS feedback loop, which inhibits the selective autophagy of afadin by suppressing the transcription of BECN1. Therefore, circROBO1 could be used not only as a potential prognostic marker but also as a therapeutic target in BC.

Sclareol, a diterpene alcohol isolated from the herbal and flavor plant clary sage (Salvia sclarea L.), is far-famed as the predominant ingredient in the refined oil of Salvia sclarea (L.). The empirical medicine of Salvia sclarea L. focused on various diseases, such as arthritis, oral inflammation, digestive system diseases, whereas the sclareol possessed more extensive and characteristic bioactivities, including anti-tumor, anti-inflammation and anti-pathogenic microbes, even anti-diabetes and hypertension. However, there is a deficiency of literature to integrate and illuminate the pharmacological attributes of sclareol based on well-documented investigations. Interestingly, sclareol has been recently considered as the potential candidate against COVID-19 and Parkinson’s disease. Accordingly, the bioactive attributes of sclareol in cancer, inflammation, even pharmacochemistry and delivery systems are reviewed for comprehensively dissecting its potential application in medicine.

To overcome the challenges of the low efficiency of artemisinin (ART) in anticancer therapy due to its poor water solubility and poor bioavailability, we constructed folate (FA)-modified erythrocyte membrane (EM)-camouflaged poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) (PFH/ART@PLGA/Fe3O4-eFA). Specifically, the inner core of these NPs is mainly composed of phase-changeable perfluorohexane (PFH), magnetic Fe3O4 and ART. In vitro experiments showed that the prepared PFH/ART@PLGA/Fe3O4-eFA was readily taken up by 4T1 cancer cells. PFH/ART@PLGA/Fe3O4-eFA was exposed to low-intensity focused ultrasound (LIFU) irradiation to induce PFH phase transition and NPs collapse, which promoted the release of ART and Fe3O4. After LIFU irradiation, the proportion of dead 4T1 cells, the level of reactive oxygen species (ROS) and the concentration of intracellular Fe2+ ions in the PFH/ART@PLGA/Fe3O4-eFA group were much higher than those in the other group, indicating that the synergistic effect between the intracellular Fe2+ ions and the released ART played a critical role in tumor cell ferroptosis by enhancing ROS generation in vitro. We demonstrated that FA-modified EM NPs could enhance the targeting and accumulation of the NPs at the tumor site in vivo. After LIFU irradiation at 3 W/m2 for 7 min, tumor growth was completely suppressed through FA-modified EM NPs collapse and the release of ART and Fe3O4, which exerted synergistic effects in inducing tumor ferroptosis. Because of these characteristics, these NPs are considered as a promising approach for the delivery of drugs with poor water solubility for efficient cancer therapy.

Triple-negative breast cancer (TNBC) is the subtype with the worst prognosis of breast cancer. Ferroptosis, a novel iron-dependent programmed cell death, has an increasingly important role in tumorigenesis and development. However, there is still a lack of research on the relationship between ferroptosis-related genes and the prognosis of TNBC. In this study, we obtained the gene expression profile of TNBC patients and matched clinical data from The Cancer Genome Atlas (TCGA) database. Univariate Cox analysis was used to screen out ferroptosis-related genes associated with TNBC prognosis. Then, the least absolute shrinkage and selection operator (LASSO) regression analysis was employed to establish a prognostic prediction model. A 15-ferroptosis-related gene prognostic prediction model was developed, which classified patients into low-risk (LR) or high-risk (HR) groups. Kaplan-Meier analysis results showed that the prognosis of the LR group was better. The receiver operating characteristic (ROC) curve also confirmed the satisfactory predictive ability of this model. Evaluation of the immune microenvironment of TNBC patients in the HR and LR group suggested these 15 ferroptosis-related genes might affect the prognosis of TNBC by regulating the tumor microenvironment. Our prognostic model can provide a theoretical basis for accurate prognosis prediction of TNBC in clinical practice.

Breast cancer ranks as the leading cause of death in lethal malignancies among women worldwide, with a sharp increase of incidence since 2008. Triple negative breast cancer (TNBC) gives rise to the largest proportion in breast cancer-related deaths because of its aggressive growth and rapid metastasis. Hence, searching for promising targets and innovative approaches is indispensable for the TNBC treatment. Maackiain (MA), a natural compound with multiple biological activities, could be isolated from different Chinese herbs, such as Spatholobus suberectus and Sophora flavescens. It was the first time to report the anti-cancer effect of MA in TNBC. MA could suppress TNBC cell proliferation, foci formation, migration, and invasion. MA also exerted a significant inhibitory effect on tumor growth of TNBC. Furthermore, MA could induce apoptosis with an increase of GADD45α and a decrease of miR-374a. In contrast, overexpressing miR-374a would result in at least partly affecting the proapoptotic effect of MA and suppressing GADD45α stimulated by MA. These results reveal the anti-TNBC effect of MA in vitro and in vivo, providing evidence for its potential as a drug candidate utilized in TNBC therapy.

Abstract Background Mucinous breast carcinoma (MBC) is a relatively rare pathological type of breast cancer. Compared with mastectomy in MBC, the effect and safety of breast‐conserving therapy (BCT) remains unclear. Therefore, we investigated the long‐term prognosis of BCT and mastectomy in T1‐2 stage mucinous breast carcinoma via the Surveillance, Epidemiology, and End Results (SEER) database. Methods Totally, 8830 patients who were diagnosed of mucinous breast carcinoma between 2004 and 2014 from SEER database were reviewed retrospectively. Cox proportional hazards model and Kaplan‐Meier method were performed for evaluating the relationship between surgical method and prognosis. Results One thousand three hundred and twenty (14.9%) patients underwent mastectomy and 7510 (85.1%) underwent BCT. The median follow‐up time was 77 months. There were more non‐Hispanic white, married, and younger ( .05).While for patients who received BCT, the use of radiotherapy showed OS benefit. Conclusions This large population‐based study indicated patients who received BCT had better prognosis than those received mastectomy in T1‐2 stage MBC, especially in patients at the age of 50‐79 years. The use of radiotherapy showed OS benefit in patients receiving BCT. Breast‐conserving therapy might be preferred over mastectomy especially in locoregional treatment of T1‐2 stage MBC.

Background: Invasive micropapillary carcinoma (IMPC) is a rare histological subtype of breast cancer. The outcome of IMPC remains controversial; we conducted a meta-analysis of propensity score matching (PSM) studies to evaluate the prognostic difference between IMPC and invasive ductal carcinoma (IDC). Methods: We searched PubMed, EMBASE and the Cochrane library for PSM studies comparing survival data between IMPC and IDC. The summarized odds ratios (ORs) and 95% confidence interval (95% CI) are calculated by STATA software utilizing fixed-effect or random-effect models, depending on the heterogeneity of the eligible studies. Results: Eight PSM studies including 2102 IMPC patients are included in the meta-analysis. Compared with IDC, IMPC has a similar overall survival (OS) (estimated OR = 0.87, 95% CI: 0.61–1.25), but a shorter relapse free survival (RFS) (estimated OR = 1.31, 95% CI: 1.06–1.61); the shorter RFS might owe to the significantly higher loco-regional recurrence rate of IMPC (estimated OR = 3.60, 95% CI: 1.99–6.52). Funnel plots and Egger’s tests are used to evaluate publication bias and the p value for OS and RFS are 0.036 and 0.564 respectively. Conclusions: Our results demonstrate that compared with IDC, IMPC exhibits a similar, even favorite OS, but a shorter RFS; and the shorter RFS might owe to the significantly higher loco-regional recurrence rate of IMPC. These results could contribute to the individualized therapy and follow-up strategies for IMPC patients.

The prognosis of breast cancer brain metastasis (BCBM) is extremely poor due to its resistance to conventional therapy. Elucidation of the molecular mechanisms of BCBM could contribute to the development of new therapeutic targets. In this study, we isolated RNA samples from primary breast cancer or BCBM, and then performed mRNA profiling. We determined that SOX2 is associated with the occurrence of BCBM and could be a predictor of BCBM. High levels of SOX2 were significantly associated with decreasing BCBM-free survival in patients. Overexpression of SOX2 in breast cancer cells enhanced cancer cell adhesion to brain microvascular endothelial cells, transendothelial migration, and in vitro blood-brain barrier (BBB) migration, whereas silencing SOX2 inhibited these events. SOX2 can increase cancer cell migration and BBB permeability by upregulating FSCN1 and HBEGF, thereby promoting BBB migration of breast cancer cells. Moreover, high levels of FSCN1 and HBEGF were significantly associated with reducing BCBM-free survival in breast cancer patients. Further study indicated that SOX2 mediates the expression of HBEGF and FSCN1 by activating AKT and β-catenin signaling pathways. Additionally, in vivo experiments showed that SOX2 promotes the development of BCBM. This study demonstrated that SOX2 promotes BCBM by upregulating the expression of FSCN1 and HBEGF.

Abstract Background Sparganosis caused by Spirometra erinaceieuropaei spargana is a zoonotic parasitic infection that has been reported in many countries, including China, Japan, Thailand and Korea, as well as European countries and the USA. The biological and clinical significance of the parasite have previously been reported. Although the genomic and transcriptomic analysis of S. erinaceieuropaei provided insightful views about the development and pathogenesis of this species, little knowledge has been acquired in terms of post-translational regulation that is essential for parasite growth, development and reproduction. Here, we performed site-specific phosphoproteomic profiling, with an aim to obtain primary information about the global phosphorylation status of spargana. Results A total of 3228 phosphopeptides and 3461 phosphorylation sites were identified in 1758 spargana proteins. The annotated phosphoproteins were involved in a variety of biological pathways, including cellular (28%), metabolic (20%) and single-organism (17%) processes. The functional enrichment of phosphopeptides by Gene Ontology analysis indicated that most spargana phosphoproteins were related to the cytoskeleton cellular compartment, signaling molecular function, and a variety of biological processes, including a molecular function regulator, guanyl-nucleotide exchange factor activity, protein kinase activities, and calcium ion binding. The highly enriched pathways of phosphorylation proteins include the phosphatidylinositol signaling system, phagosome, endocytosis, inositol phosphate metabolism, terpenoid backbone biosynthesis, and peroxisome. Domain analysis identified an EF-hand domain and pleckstrin homology domain among the key domains. Conclusions To our knowledge, this study performed the first global phosphoproteomic analysis of S. erinaceieuropaei. The dataset reported herein provides a valuable resource for future studies on the signaling pathways of this important zoonotic parasite.

Abstract Background Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with highly invasive ability and metastatic nature to the lymph nodes. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis and progression. However, their roles in TNBC lymph node metastasis remains rarely studied. Methods The expression of lncRNA highly upregulated in metastatic TNBC (HUMT) in cell lines and tissues was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). RNA immunoprecipitation (RIP) and RNA pulldown were used to verify the interaction between lncRNA and protein. Chromatin immunoprecipitation (CHIP) and dCas9-gRNA-guided chromatin immunoprecipitation (dCas9-CHIP) were conducted to identify the specific binding site of HUMT-YBX1 complex. Western blot was used to detect the downstream of HUMT. Results HUMT was significantly upregulated in lymph node invasive cells and predicted poorer clinical prognosis. Functional study indicated that HUMT promoted lymphangiogenesis and lymph node metastasis. Bioinformatic analysis and qRT-PCR showed that the high expression of HUMT was correlated with the hypomethylation status of its promoter region. Further, HUMT recruited Y-box binding protein 1 (YBX1) to form a novel transcription complex and activated the expression of forkhead box k1 (FOXK1), thus enhancing the expression of vascular endothelial growth factor C (VEGFC). The therapeutic value was further validated in patient-derived xenograft (PDX) models, and a combined marker panel exhibited a better prognostic value for TNBC in receiver operating characteristic (ROC) analysis. Conclusions Our study identified a novel TNBC lymph node metastasis-associated lncRNA, which promoted TNBC progression and indicated a novel biomarker and potential therapeutic target for TNBC lymph node metastasis.

Immune system disorder is associated with metastasis of triple-negative breast cancers (TNBCs). A robust, individualized immune-related genes (IRGs)-based classifier was aimed to develop and validate in our study to precisely estimate the axillary lymph node (ALN) status preoperatively in patients with early-stage TNBC. We first analyzed RNA sequencing profiles in TNBC patients from The Cancer Genome Atlas database by using bioinformatics approaches, and screened 23 differentially expressed IRGs. A 9-gene panel was generated with an area under the curve (AUC) of 0.77 [95% confidence interval (95% CI), 0.68–0.87]. We detected the 9 ALN-status-related IRGs in the training set (n = 133) and developed a reduced and optimized five-IRGs signature, which effectively distinguished TNBC patients with ALN metastasis (AUC, 0.80; 95% CI, 0.65–0.86), and was superior to preoperative ultrasound-based ALN status (AUC, 0.73; 95% CI, 0.53–0.93). Predictive efficiency (AUC, 0.77; 95% CI 0.61–0.93) of this five-IRGs signature was validated in the validation set (n = 81). Furthermore, IRGs nomogram incorporated IRGs signature with US-based ALN status showed higher ALN status prediction efficacy than US-based ALN status and five-IRGs signature alone in both training and validation sets. IRGs nomogram may aid in identifying patients who can be exempted from axillary surgery.Novelty and impact: An immune-related genes (IRGs) nomogram was first developed and externally validated in our study, which incorporated the IRGs signature with ultrasound (US)-based axillary lymph nodes (ALN) status. IRGs nomogram is superior to IRGs signature alone for preoperative estimation of ALN metastasis in patients with triple-negative breast cancer (TNBC). It is a favourable biomarker for preoperatively predicting ALN metastasis risk and may aid in clinical decision-making in early-stage TNBCs.

Accumulating evidence indicates that circular RNAs (circRNAs) are vital regulators of various biological functions involved in the progression of multiple cancers. Circular F-box and WD repeat domain containing 7 (circFBXW7) (hsa_circ_0001451) has been reported to act as a tumor suppressor by encoding a novel protein in glioma; however, its functions and mechanisms in triple-negative breast cancer (TNBC) remain elusive. In the current study, we validated by qRT-PCR that circFBXW7 was downregulated in TNBC cell lines and found that low expression of circFBXW7 was associated with poorer clinical outcomes. circFBXW7 expression was negatively correlated with tumor size and lymph node metastasis, and it was an independent prognostic factor for TNBC patients. We performed cell proliferation, colony formation, transwell, wound-healing, and mouse xenograft assays to confirm the functions of circFBXW7. Overexpression of circFBXW7 obviously inhibited cell proliferation, migration, and tumor growth in both in vitro and in vivo assays. Luciferase reporter assays and RNA immunoprecipitation assays revealed that circFBXW7 serves as a sponge of miR-197-3p and suppresses TNBC growth and metastasis by upregulating FBXW7 expression. In addition, the FBXW7-185aa protein encoded by circFBXW7 inhibited the proliferation and migration abilities of TNBC cells by increasing the abundance of FBXW7 and inducing c-Myc degradation. In summary, our research demonstrated that circFBXW7 sponges miR-197-3p and encodes the FBXW7-185aa protein to suppress TNBC progression through upregulating FBXW7 expression. Thus, circFBXW7 may act as a therapeutic target and prognostic biomarker for TNBC. Keywords: circular RNAs, circFBXW7, FBXW7, competitive endogenous RNAs, triple negative breast cancer

Abstract In order to find out the optimal concentration of ionic liquid to lower the cost of inhibiting coal spontaneous combustion, effects of aliphatic hydrocarbons, hydrogen bonds, and some structural parameters of coal samples treated with low‐concentration ionic liquids were analyzed through Fourier‐transform infrared spectroscopy (FTIR) and temperature‐programmed experiments. Meanwhile, the changes of index gases in the heating process were observed by the temperature‐programmed method. The results show that the contents of aliphatic hydrocarbons in the treated coal samples decrease remarkably, so does the length of aliphatic chain CH2/CH3; besides, the amount of CO produced also decreases to some extent. When the mass concentration ratio is 1:10, HB‐tc, BB‐tc, AC‐tc, and BN‐tc can reduce the spatial structure and enhance the structural stability of aromatic clusters in coal. The CO concentrations of 1:2 HB‐tc and 1:10 AC‐tc are obviously lower than that of raw coal, indicating their better inhibitory effects. The inhibitory effect of HB‐tc decreases with the decrease in concentration. With the rise of temperature, the effect of concentration on the inhibition of CO production gradually weakens at 180°C and 200°C. AC‐tc achieves the optimum inhibitory effect near 1:10 mass concentration ratio.

The simultaneous detection of two different biomarkers for the point-of-care diagnosis of major diseases, such as Alzheimer’s disease (AD), is greatly challenging. Due to the outstanding photoluminescence (PL) properties of quantum dots (QDs), a high-quality CdSe/CdS/ZnS QD-based fluorescence resonance energy transfer (FRET) aptasensor for simultaneously monitoring the amyloid-β oligomers (AβO) and tau protein was proposed. By engineering the interior inorganic structure and inorganic–organic interface, water-soluble dual-color CdSe/CdS/ZnS QDs with a near-unity PL quantum yield (>90%) and mono-exponential PL decay dynamics were generated. The π–π stacking and hydrogen bond interaction between the aptamer-functionalized dual-color QDs and gold nanorods@polydopamine (Au NRs@PDA) nanoparticles resulted in significant fluorescence quenching of the QDs through FRET. Upon the incorporation of the AβO and tau protein, the fluorescence recovery of the QDs-DNA/Au NRs@PDA assembly was attained, providing the possibility of simultaneously assaying the two types of AD core biomarkers. The lower detection limits of 50 pM for AβO and 20 pM for the tau protein could be ascribed to the distinguishable and robust fluorescence of QDs and broad spectral absorption of Au NRs@PDA. The sensing strategy serves as a viable platform for the simultaneously monitoring of the core biomarkers for AD and other major diseases.